Roger J. Narayan

Nanoporous membranes for medical and biological applications.

Synthetic nanoporous materials have numerous potential biological and medical applications that involve sorting, sensing, isolating, and releasing biological molecules. Nanoporous systems engineered to mimic natural filtration systems are actively being developed for use in smart implantable drug delivery systems, bioartificial organs, and other novel nano-enabled medical devices. Recent advances in nanoscience have made it possible to precisely control the morphology as well as physical and chemical properties of the pores in nanoporous materials that make them increasingly attractive for regulating and sensing transport at the molecular level. In this work, an overview of nanoporous membranes for biomedical applications is given. Various in vivo and in vitro membrane applications, including biosensing, biosorting, immunoisolation, and drug delivery, are presented. Different types of nanoporous materials and their fabrication techniques are discussed with an emphasis on membranes with ordered pores. Desirable properties of membranes used in implantable devices, including biocompatibility and antibiofouling behavior, are discussed. The use of surface modification techniques to improve the function of nanoporous membranes is reviewed. Despite the extensive research carried out in fabrication, characterization, and modeling of nanoporous materials, there are still several challenges that must be overcome in order to create synthetic nanoporous systems that behave similarly to their biological counterparts.

Three-dimensional laser micro- and nano-structuring of acrylated poly(ethylene glycol) materials and evaluation of their cytoxicity for tissue engineering applications.

The natural cell environment is characterized by complex three-dimensional structures, which contain features at multiple length scales. Many in vitro studies of cell behavior in three dimensions rely on the availability of artificial scaffolds with controlled three-dimensional topologies. In this paper, we demonstrate fabrication of three-dimensional scaffolds for tissue engineering out of poly(ethylene glycol) diacrylate (PEGda) materials by means of two-photon polymerization (2PP). This laser nanostructuring approach offers unique possibilities for rapid manufacturing of three-dimensional structures with arbitrary geometries. The spatial resolution dependence on the applied irradiation parameters is investigated for two PEGda formulations, which are characterized by molecular weights of 302 and 742. We demonstrate that minimum feature sizes of 200nm are obtained in both materials. In addition, an extensive study of the cytotoxicity of the material formulations with respect to photoinitiator type and photoinitiator concentration is undertaken. Aqueous extracts from photopolymerized PEGda samples indicate the presence of water-soluble molecules, which are toxic to fibroblasts. It is shown that sample aging in aqueous medium reduces the cytotoxicity of these extracts; this mechanism provides a route for biomedical applications of structures generated by 2PP microfabrication and photopolymerization technologies in general. Finally, a fully biocompatible combination of PEGda and a photoinitiator is identified. Fabrication of reproducible scaffold structures is very important for systematic investigation of cellular processes in three dimensions and for better understanding of in vitro tissue formation. The results of this work suggest that 2PP may be used to polymerize poly(ethylene glycol)-based materials into three-dimensional structures with well-defined geometries that mimic the physical and biological properties of native cell environments.

Stiff subcircuit islands of diamondlike carbon for stretchable electronics

Stretchable electronics on elastomeric substrates requires fragile and brittle device materials to be placed on stiff, mechanical distinct subcircuit islands. We deposited a diamondlike carbon (DLC) film at room temperature on a silicone substrate by pulsed laser ablation, and patterned the film into an array of 200×200μm2 islands. When the substrate was uniaxially stretched to a strain of 25%, the islands remained adherent to the substrate and only deformed by ∼5%, while the exposed substrate stretched by more than 30%. A row of 11 DLC islands interconnected with gold stretchable metallization maintained end-to-end electrical conduction during a mechanical cycle to 20% tensile strain. This demonstration of electrically interconnected stiff islands on silicone illustrates two important steps toward fully integrated, elastically stretchable electronics.

Stereolithography in tissue engineering

Several recent research efforts have focused on use of computer-aided additive fabrication technologies, commonly referred to as additive manufacturing, rapid prototyping, solid freeform fabrication, or three-dimensional printing technologies, to create structures for tissue engineering. For example, scaffolds for tissue engineering may be processed using rapid prototyping technologies, which serve as matrices for cell ingrowth, vascularization, as well as transport of nutrients and waste. Stereolithography is a photopolymerization-based rapid prototyping technology that involves computer-driven and spatially controlled irradiation of liquid resin. This technology enables structures with precise microscale features to be prepared directly from a computer model. In this review, use of stereolithography for processing trimethylene carbonate, polycaprolactone, and poly(d,l-lactide) poly(propylene fumarate)-based materials is considered. In addition, incorporation of bioceramic fillers for fabrication of bioceramic scaffolds is reviewed. Use of stereolithography for processing of patient-specific implantable scaffolds is also discussed. In addition, use of photopolymerization-based rapid prototyping technology, known as two-photon polymerization, for production of tissue engineering scaffolds with smaller features than conventional stereolithography technology is considered.

Semiconductor-metal transition characteristics of VO2 thin films grown on c- and r-sapphire substrates

We have made a comparative study of epitaxial growth of VO2 thin films on c-cut (0001) and r-cut (11¯02) sapphire substrates, and the semiconductor to metal transition (SMT) characteristics of these films have been correlated with their structural details. On c-sapphire, VO2 grows epitaxially in (002) orientation. These (002) oriented VO2 films have 60° twin boundaries due to three equivalent in-plane orientations. The epitaxial VO2 films on r-sapphire consisted of two orientations, namely (200) and (2¯11). The coexistence of these two orientations of VO2 has been explained on the basis of similarity of atomic arrangements in (200) and (2¯11) planes. The thermal hysteresis (ΔH), sharpness of the transition (ΔT), and the transition temperature for VO2 films on c-sapphire were found to be 4.8, 8.5, and 72.6 °C, respectively, which were higher than the corresponding values of 3.3, 5.4, and 60.3 °C for films on r-sapphire. The SMT temperature for VO2 films on c-sapphire was close to the bulk value of 68.0 °C....

Diamond, diamond-like and titanium nitride biocompatible coatings for human body parts

Abstract A new approach is proposed for fabricating human body parts that last longer and are more biocompatible than those presently available. In this approach, bulk material is chosen that has desirable mechanical properties (low modulus, high strength, high ductility and high fatigue strength) and then this material is coated with highly corrosion- and erosion-resistant and totally biocompatible layers. As an example, we have investigated diamond, TiN, diamond/diamond-like, and diamond/TiN coatings on Ti−6wt.%Al−4wt.%V alloy used for hip prosthesis. This alloy has desirable mechanical properties but the toxicity of vanadium and the neurological disorders associated with aluminum have raised some concerns. To overcome this problem, we have developed a laser physical vapor deposition method to form TiN and diamond-like coatings, and a hot-filament-assisted chemical vapor desposition method to form diamond layers. Cementless diamond-coated hip prostheses of titanium alloys are expected to last approximately ten times longer or more compared with the polymethylmethacrylate-cement-coated CoCr prostheses used at present. The microstructure of diamond films can be controlled by substrate and deposition variables. The microstructures of these films have been investigated using optical and scanning electron microscopy, chemical composition by Auger electron spectroscopy, structure by X-ray diffraction, and atomic arrangements (lattice vibration) characteristics by Raman spectroscopy. The average grain size of diamond films varied from 0.5 to 2.0 μm, and the diamond-like films were amorphous. The average grain size of TiN films was found to vary from 10 to 20 nm. The diamond films showed characteristics Raman peak at 1332 cm −1 (sp 3 bonding), and diamond-like films contained 1350 and 1580 cm −1 Raman peaks (a mixture of sp 2 and sp 3 bonding). The mechanical properties and adhesion characteristics of these films together with biocompatibility issues are discussed for titanium alloy hip prosthesis.

Fabrication of microscale medical devices by two-photon polymerization with multiple foci via a spatial light modulator

Two-photon polymerization is an appealing technique for producing microscale devices due to its flexibility in producing structures with a wide range of geometries as well as its compatibility with materials suitable for biomedical applications. The greatest limiting factor in widespread use of two-photon polymerization is the slow fabrication times associated with line-by-line, high-resolution structuring. In this study, a recently developed technology was used to produce microstructures by two-photon polymerization with multiple foci, which significantly reduces the production time. Computer generated hologram pattern technology was used to generate multiple laser beams in controlled positions from a single laser. These multiple beams were then used to simultaneously produce multiple microstructures by two-photon polymerization. Arrays of micro-Venus structures, tissue engineering scaffolds, and microneedle arrays were produced by multifocus two-photon polymerization. To our knowledge, this work is the first demonstration of multifocus two-photon polymerization technology for production of a functional medical device. Multibeam fabrication has the potential to greatly improve the efficiency of two-photon polymerization production of microscale devices such as tissue engineering scaffolds and microneedle arrays.

Laser direct writing of micro- and nano-scale medical devices

Laser-based direct writing of materials has undergone significant development in recent years. The ability to modify a variety of materials at small length scales and using short production times provides laser direct writing with unique capabilities for fabrication of medical devices. In many laser-based rapid prototyping methods, microscale and submicroscale structuring of materials is controlled by computer-generated models. Various laser-based direct write methods, including selective laser sintering/melting, laser machining, matrix-assisted pulsed-laser evaporation direct write, stereolithography and two-photon polymerization, are described. Their use in fabrication of microstructured and nanostructured medical devices is discussed. Laser direct writing may be used for processing a wide variety of advanced medical devices, including patient-specific prostheses, drug delivery devices, biosensors, stents and tissue-engineering scaffolds.

Microneedle array-based carbon paste amperometric sensors and biosensors

The design and characterization of a microneedle array-based carbon paste electrode towards minimally invasive electrochemical sensing are described. Arrays consisting of 3 × 3 pyramidal microneedle structures, each with an opening of 425 µm, were loaded with a metallized carbon paste transducer. The renewable nature of carbon paste electrodes enables the convenient packing of hollow non-planar microneedles with pastes that contain assorted catalysts and biocatalysts. Smoothing the surface results in good microelectrode-to-microelectrode uniformity. Optical and scanning electron micrographs shed useful insights into the surface morphology at the microneedle apertures. The attractive performance of the novel microneedle electrode arrays is illustrated in vitro for the low-potential detection of hydrogen peroxide at rhodium-dispersed carbon paste microneedles and for lactate biosensing by the inclusion of lactate oxidase in the metallized carbon paste matrix. Highly repeatable sensing is observed following consecutive cycles of packing/unpacking the carbon paste. The operational stability of the array is demonstrated as well as the interference-free detection of lactate in the presence of physiologically relevant levels of ascorbic acid, uric acid, and acetaminophen. Upon addressing the biofouling effects associated with on-body sensing, the microneedle carbon paste platform would be attractive for the subcutaneous electrochemical monitoring of a number of physiologically relevant analytes.

Fabrication of Polymer Microneedles Using a Two-Photon Polymerization and Micromolding Process

Background: Microneedle-mediated drug delivery is a promising method for transdermal delivery of insulin, incretin mimetics, and other protein-based pharmacologic agents for treatment of diabetes mellitus. One factor that has limited clinical application of conventional microneedle technology is the poor fracture behavior of microneedles that are created using conventional materials and methods. In this study polymer microneedles for transdermal delivery were created using a two-photon polymerization (2PP) microfabrication and subsequent polydimethylsiloxane (PDMS) micromolding process. Methods: Solid microneedle arrays, fabricated by means of 2PP, were used to create negative molds from PDMS. Using these molds microneedle arrays were subsequently prepared by molding eShell 200, a photo-reactive acrylate-based polymer that exhibits water and perspiration resistance. Results: The eShell 200 microneedle array demonstrated suitable compressive strength for use in transdermal drug delivery applications. Human epidermal keratinocyte viability on the eShell 200 polymer surfaces was similar to that on polystyrene control surfaces. In vitro studies demonstrated that eShell 200 microneedle arrays fabricated using the 2PP microfabrication and PDMS micromolding process technique successfully penetrated human stratum corneum and epidermis. Conclusions: Our results suggest that a 2PP microfabrication and subsequent PDMS micromolding process may be used to create microneedle structures with appropriate structural, mechanical, and biological properties for transdermal drug delivery of insulin and other protein-based pharmacologic agents for treatment of diabetes mellitus.